The macrophage-stimulating activity of mycoplasma has been known for a relatively long time; see Loewenstein et al. in Cellular Immunology, 77 (1983) 290-297. It has also been assumed and formally proved that lipoproteins from mycoplasma exhibit such an activity; see Herbelin et al. in Infect. lmmun., 62 (1994) 4690-4694 and Mxc3xchlradt et al. in Biochemistry, 35 (1996) 7781-7786. Lipoproteins from Gram-negative bacteria and analogues of those lipoproteins are likewise immunomodulators and have been described specifically as macrophage activators; see Melchers et al. in J. Exp. Med., 142 (1975) 473-482 and Hoffmann et al. in Immunobiol., 177 (1988) 158-170. Those species of lipoproteins carry an N-terminal S-(2,3-dihydroxypropyl)-cysteine group (Dhc) having three long-chain fatty acids, of which two are bonded in the form of esters and one is bonded in the form of an amide.
Lipoproteins and synthetic lipopeptide analogues have a half-maximum effective concentration (Max/2) of approximately 10xe2x88x927 M; see Melchers et al. in J. Exp. Med., 142 (1975) 473-482 and Hoffmann et al in Biol. Chem. Hoppe Seyler, 370 (1989) 575-582.
Synthetic analogues without the amide fatty acid have a half-maximum effective concentration (Max/2) of approximately 10xe2x88x928M; see Metzger et al. in J. Peptide Scie., 3 (1995) 184-190. Furthermore, in Tertahedron, 45 (1989) 6331-6360, 6352, Baschang described a taurine-modified lipoprotein (sodium sulphonate; CGP-31362) which, according to Dong et al. in J. Exp. Med., 177 (1993) 1071-1077. still has macrophage-activating action as from 1 to 10 ng/ml of from 1 to 10xc3x9710xe2x88x929 M. Finally, in J. Peptide Scie., 3 (1995) 184-190, Metzge describes a Dhc peptide having the amino acid sequence CFE PPP ATT T (SEQ ID NO: 2), two palmitoyl groups being bonded to the 2,3-dihydroxypropyl group. The half-maximum effective concentration (Max/2) of that known peptide is 16 ng/ml or 10xc3x9710xe2x88x929 M.
There is, however, still a need for effective lipopeptides.
According to the invention there is now proposed a S-(2,3-dihydroxypropyl)-cysteine peptide having two fatty acids, which may be identical or different, bonded to the dihydroxypropyl group in the form of esters, the peptide having the following amino acid sequences (SEQ ID NO 1):
or an amino acid sequence that is identical to the sequence (SEQ ID NO 1) except that the two N-terminal amino acids in positions 2 and, optionally, 3 are missing and/or one or two C-terminal amino acids have been deleted.
According to the invention, the two fatty acid radicals may have the formula Rxe2x80x94COxe2x80x94, wherein R is a C7-C25-alkyl, C7-C25-alkenyl or C7-C25-alkynyl radical, unsaturated radicals preferably being present in the cis configuration. Examples of C7-C25-alkyl, -alkenyl and -alkynyl radicals are C16 and C18 radicals.
According to the invention there is also provided a composition comprising a S-(2,3-dihydroxypropyl)-cysteine peptide according to the invention together with a conventional carrier and/or adjuvant. The composition according to the invention can be used for stimulating the synthesis of antibodies, for preventing infections (anti-infective activity), as an immunostimulant against tumours, for activating macro-phages, for developing tolerance towards endotoxins or in the case of septic shock, especially in the case of Gram-negative bacteria, or as a vaccine adjuvant (admixture with a vaccine).
According to the invention, S-(2,3-dihydroxypropyl)-cysteine peptides can be prepared in a fully synthetic manner. The person skilled in the art can proceed analogously to the cited prior art. Reference is made also to DE 35 46 150 A1, DE 37 00 173 A1, DE 38 13 821 A1, DE 41 19 856 A1 and DE 43 29 309 A1.